Global Trials Focus

Summary: : In this single-center study, 68 children on maintenance hemodialysis were randomized to receive either a 40-minute thrice weekly exercise program during hemodialysis for 2 months or routine care. A trained physical therapy researcher taught the exercises, including lower limb stretches (10 repetitions per muscle) during the first 20 minutes of the second hour of dialysis, followed by isometric strength training (3-5 second holds, 10 repetitions per exercise) during the first 20 minutes of the third hour. The primary outcome was quality of life (QoL) at 2 months, which was assessed using the Pediatric Quality of Life (PedsQL) scale that looked at four domains: physical, emotional, social functioning, and school performance. Majority of children were male (65%), aged 14-18 years (48%), with congenital anomalies as the leading cause of kidney failure (38%), and had been on hemodialysis for 1-5 years (53%). After 2 months, the intervention group demonstrated a significant improvement in the total PedsQL score (increased from 635.0±502.26 to 1648.33±468.62; p=0.001), whilst the control group remained unchanged (629.69±496.21 to 676.56±520.78). This improvement was apparent across all four domains in the intervention group: physical function increased from 132.50 to 483.33, emotional functioning from 141.67 to 356.67, social functioning from 195.83 to 419.17, and school performance from 165.0 to 389.17. In contrast, the control group showed minimal change in these domains. At baseline, most children also had poor QoL (83.3% intervention group and 83.4% control group); however, after 2 months, this reduced to 20% in the intervention group and remained unchanged in the control group (86.7%).

Comment: Children with chronic kidney disease and kidney failure experience reduced physical activity and QoL. While exercise has shown some benefits in improving QoL and physical performance in adults on hemodialysis, similar research in children is limited, and adult findings cannot be directly applied to younger populations. This study was successful in getting children to exercise during hemodialysis, demonstrating that a simple, cheap intervention involving muscle stretching and isometric exercises during hemodialysis significantly improved total QoL scores and positively impacted all domains. Limitations of this study include its lack of generalizability given the single-centre setting, small sample size, lack of objective physical fitness measures such as assessments of cardiorespiratory endurance or muscular strength, and a short two month follow up. Thus, it is not clear if long-term engagement in children is sustainable, and if the benefits attenuate or continue to improve. Further studies should explore different forms of exercise across larger populations with different dialysis modalities, utilizing objective assessment tools and strategies like exercise gamification to enhance adherence and evaluate long-term benefits.

Summary: This study was a Phase 2b, double-blind, randomized controlled run-in trial assessing the effect of selonsertib compared to placebo on estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes and CKD. Patients were stratified by an eGFR of 20 to <60 mL/min/1.73 m², a urine albumin-to-creatinine ratio of 150– 5000 mg/g, and the use of the maximum tolerated dose of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The trial had a 4 week run-in period to establish baseline eGFR while on selonsertib. Out of 961 patients screened, 384 patients entered the run-in period and 310 patients were randomized (154 in the selonsertib group and 156 in the placebo group). The study population had a mean age of 65 and 69% were male. Ethnically, 51% were White, 27% Asian, 17% Black, and 14% were Hispanic. The primary outcome was the change in eGFR from the run-in baseline value over a maximum of 84 weeks, while secondary outcomes included the proportion of patients with clinical kidney events (≥40% decline in eGFR compared to run-in, kidney failure, or death due to kidney disease). Results showed the mean difference between selonsertib and placebo eGFR slopes at week 84 was 1.20 ml/min per 1.73 m2 per year (95% confidence interval, 20.41 to 2.81; P = 0.14). However, kidney clinical events occurred in 17% of patients on selonsertib versus 12% on placebo (difference 4.7%, 95% CI: -26.3% to 15.9%), with AKI being the most common adverse event (11.0 vs. 5.9 per 100 patient-years, respectively).

Comment: Diabetic kidney disease progression involves the activation of apoptosis signal-regulating kinase 1 (ASK-1), which drives inflammation and fibrosis through oxidative stress. Selonsertib, a novel ASK-1 inhibitor, was evaluated in this study for its potential to slow diabetic kidney disease progression. Patients taking selonsertib had a lower eGFR decline but were more likely to reach a composite kidney outcome and report AKI. Key insights include the more pronounced benefit in patients with lower baseline eGFR and a numerically lower incidence of cardiovascular events in those receiving selonsertib. The study’s limitations include its likely underpowered sample size, the impact of the run-in period on outcomes, and the potential effects of incomplete run-in participation. Despite these limitations, this study lays critical groundwork for future, larger-scale trials of selonsertib in this population.

Summary: 281 recipients of a first or second kidney transplant from a living or deceased donor who had no pre transplant donor-specific antibodies (DSA) and ≥ 1 human leukocyte antigen (HLA) mismatch with their donor were included in a 5-year multicenter, prospective, Phase 3b trial evaluating treatment outcomes with standard (STD) or low (LOW) dose prolonged-release tacrolimus (TAC) combined with Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEis/ARBs) or other antihypertensive therapy (OAHT). Until Month 6, target TAC trough concentration was 5 ± 1 ng/mL in the LOW intervention group, 12 ± 2 ng/mL during Weeks 1 and 2, 10 ± 2 ng/mL from Week 3 to Month 3, and 8 ± 2 ng/mL from Month 4 to Month 6 in the STD intervention group. TAC trough targets and dosing after Month 6 were at the investigators’ discretion in both groups. Patient survival was 95.7% and was comparable between groups. The overall graft survival rate at 5 years was 94.3% (89.7%) in the LOW+OAHT group, 94.4% in the LOW+ACEi/ARB group, 95.8% in the STD+ACEi/ARB group, and 97.1% in the STD+OAHT group (p = NS). Class II de novo donor-specific antibodies (dnDSA) were higher in the LOW+OAHT group than in the other groups. However, these differences were not statistically significant. Graft function, blood pressure (BP), and proteinuria were similar between the groups. Between 2 and 5 years, there was a 2-fold or higher increase in the use of ACEi/ARB in patients randomized initially to OAHT, primarily because of hypertension and proteinuria. No unexpected safety findings were recorded.

Comment: Tacrolimus, a key component of modern immunosuppressive protocols in kidney transplantation, comes with several side effects including reduced graft survival. Therefore, finding ways to reduce exposure to tacrolimus while maintaining its effectiveness is critically important. ACEis/ ARBs have been shown to have potential kidney protective effects. This study supports a tailored approach to tacrolimus dosing suggesting that using low-dose tacrolimus and ACEi/ARB co-administration may be a promising and safe treatment approach for kidney transplant recipients. Notably, in this study, patients initially randomized to receive OAHT eventually switched to ACEi/ARB, primarily due to issues like hypertension and proteinuria. The dropout rate was also high, reaching 25%. Future studies should consider performing late kidney biopsies to assess differences in tacrolimus-associated interstitial fibrosis and tubular atrophy, focusing not just on its immunological effects measured by donor-specific antibodies. Longer followup is mandatory.

Summary: HED-start was a positive-skills psychology intervention, targeting incident hemodialysis (HD) patients (<6 months maintenance dialysis, consisting of 4 group sessions covering different topics (self-management, life skills, goal setting). A total of 147 participants from 18 centers in Singapore were randomized 2:1 to the HED-start group or usual care. The primary outcome was depression and anxiety, measured by a 14-item scale with higher scores indicating more severe psychological symptoms (Hospital Anxiety and Depression Scale, HADS). The mean age of participants was 60.85 ± 10.36 years with more elderly patients presentation in usual care group, 34% were female. Groups were well balanced for education, relationship and employment status, and household income. Postintervention assessment was performed 3 months after randomization. The change in total HADS score from baseline to end of follow-up was insignificant in the HED-start and usual care groups (12.24 vs 9.84 and 10.39 vs 9.98, p=0.090), which can be explained by the absence of changes in anxiety symptoms, while depression scores were significantly different (6.28 vs 5.05 and 4.8 vs 5.1, p=0.032). In terms of secondary outcomes, positive effects were demonstrated in the Benefit Finding Scale, both in the acceptance and personal growth domains, the World Health Organization Quality of Life instrument and the Health Education Impact Questionnaire. The drop-out rate was similar between two groups, 57.7% of patients completed all 4 sessions.

Comment: The transition to dialysis can be emotionally challenging for patients, often causing anxiety and depression that may go underestimated unless severe. Although the primary outcome was not achieved, this study demonstrated beneficial effects of positive life skills on psychological adjustment in patients newly initiated on HD. The lack of significant improvement in anxiety may be attributed to protocol violations during the COVID-19 pandemic. Future trials involving more diverse ESKD cohorts are needed to evaluate long-term changes comprehensively.

Summary: This study was a double-blind, randomized controlled feasibility trial assessing the effect of cooled dialysate (35°C) versus standard dialysate (36.5°C) on cognition in hemodialysis (HD) patients. Of the 334 patients screened, 160 were eligible, and 43 were randomized (20 in the standard care group and 23 in the intervention group). The study population had a median age of 68 years (IQR: 59–77), and 67% were male. Ethnically, 63% were Caucasian, 14% Asian, and 23% African. The primary outcome was the change in Montreal Cognitive Assessment (MoCA) score over 12 months, while secondary outcomes included intradialytic hypotension (IDH), quality of life (AQoL-6D), depression (HADS), and computerized cognitive performance (Cogstate). Results showed no significant difference in MoCA score changes between groups (Standard: 1.0, 95% CI: -2.8 to 3.0, p = 0.755; Intervention: -2.0, 95% CI: -1.0 to -4.0, p = 0.047). Similarly, there were no significant differences in secondary outcomes, including IDH episodes, depression, anxiety, quality of life, recovery time, and Cogstate scores. The study faced a 27% dropout rate, primarily due to COVID-19 restrictions and the burden of attending extra non-dialysis day visits. Despite these challenges, low-temperature dialysis was well tolerated, with minimal reports of cold-related discomfort.

Comment: Cognitive impairment is a common, under-recognized concern in HD patients, with few effective interventions. This study explores cooled dialysate as a neuroprotective strategy due to its benefits in reducing intradialytic hypotension thereby preserving brain white matter. While no clear cognitive benefit was observed over 12 months, the trial informs future research on feasibility and tolerability. Key takeaways include the need for cognitive assessments during dialysis and the feasibility of using Cogstate in this population. Limitations include the exclusion of non-English speakers, MoCA’s limited sensitivity and challenges in collecting qualitative data. Despite these, the study lays the groundwork for larger trials in diverse populations.